Novel alkanoic acid derivaties

ABSTRACT

There are provided according to the invention compounds of the formula (I) or a salt or solvate thereof, wherein: n represents an integer 1 to 6; N represents an integer 1 to 15; R 1  represents (CO) x C 1-9 alkyl or (CO) x C 1-9 fluoroalkyl, which fluoroalkyl moiety contains at least 1 fluorine atom and not more than 3 consecutive perfluorocarbon atoms wherein x represents 0 or 1; and R 2  and R 3  independently represent C 1-3 alkyl or hydrogen. There are also provided pharmaceutical aerosol formulations employing said compounds as suspension stabilising agents.

[0001] This invention relates to novel compounds having surfactantproperties and aerosol formulations thereof for use in theadministration of medicaments by inhalation.

[0002] The use of aerosols to administer medicaments has been known forseveral decades. Such aerosols generally comprise the medicament, one ormore chlorofluorocarbon propellants and either a surfactant or aco-solvent, such as ethanol. The most commonly used aerosol propellantsfor medicaments have been propellant 11 (CCl₃F) and/or propellant 114(CF₂ClCF₂Cl) with propellant 12 (CCl₂F₂). However these propellants arenow believed to provoke the degradation of stratospheric ozone and thereis thus a need to provide aerosol formulations for medicaments whichemploy so called “ozone-friendly” propellants.

[0003] A class of propellants which are believed to have minimalozone-depleting effects in comparison to conventionalchlorofluorocarbons comprise fluorocarbons and hydrogen-containingchlorofluorocarbons, and a number of medicinal aerosol formulationsusing such propellant systems are disclosed in, for example, EP0372777,WO91/04011, WO91/11173, WO91/11495 and WO91/14422. These applicationsare all concerned with the preparation of pressurised aerosols for theadministration of medicaments and seek to overcome the problemsassociated with the use of the new class of propellants, in particularthe problems of stability associated with the pharmaceuticalformulations prepared. The applications all propose the addition of oneor more of adjuvants such as alcohols, alkanes, dimethyl ether,surfactants (including fluorinated and non-fluorinated surfactants,carboxylic acids, polyethoxylates etc) and even conventionalchlorofluorocarbon propellants in small amounts intended to minimisepotential ozone damage.

[0004] It is essential that the prescribed dose of aerosol medicationdelivered from the MDI to the patient consistently meets thespecifications claimed by the manufacturer and comply with therequirements of the FDA and other regulatory authorities. That is, everydose dispensed from the can must be the same within close tolerances.Therefore it is important that the formulation be substantiallyhomogenous throughout the administered dose at the time of actuation ofthe metering valve.

[0005] In the case of suspension formulations, to control aggregation offine particles, and thereby influence the dispersability of thesuspension it is well established in the art that fluorinatedsurfactants may be used to stabilise micronised drug suspensions influorocarbon propellants such as 1,1,1,2-tetrafluoroethane (P134a) or1,1,1,2,3,3,3-heptafluoro-n-propane (P227), see for example U.S. Pat.No. 4,352,789, U.S. Pat. No. 5,126,123, U.S. Pat. No. 5,376,359, U.S.application Ser. No. 09/580,008, WO91/11173, WO91/14422, WO92/00062 andWO96/09816.

[0006] WO92/00061 discloses non-fluorinated surfactants for use withfluorocarbon propellants. Surprisingly, the applicants have now foundthat a particular group of novel non-fluorinated and low fluorinecontent compounds with good surfactant properties may be used to preparenovel aerosol formulations, and can b advantageous in terms of improvingthe stability of the aerosol formulation by reducing drug deposition,increasing shelf life and the like. In addition the compounds of theinvention are adequately soluble in the fluorocarbon orhydrogen-containing chlorofluorocarbon propellants or mixtures thereof,obviating the need to use a polar adjuvant.

[0007] Thus, in one aspect the invention provides a compound of thegeneral formula (I)

[0008] or a salt or solvate thereof, wherein:

[0009] n represents an integer 1 to 6;

[0010] N represents an integer 1 to 15;

[0011] R¹ represents —(CO)_(x)C₁₋₉alkyl or —(CO)_(x)C₁₋₉ fluoroalkyl,which fluoroalkyl moiety contains at least 1 fluorine atom and not morethan 3 consecutive perfluorocarbon atoms wherein x represents 0 or 1;and

[0012] R² and R³ independently represent C₁₋₃alkyl or hydrogen.

[0013] Preferably n represents an integer 1 to 4, especially 1.Preferably N represents an integer 1 to 12, especially 2 to 9. Anotherpreferred range for N is 1 to 8, especially 1 to 6, for example, 3 to 6.

[0014] Preferably x represents 0.

[0015] Examples of group R¹ include —(CH₂)₃CF₂CF₃, —CH₂CF₂CF₃, —CH₂CF₃,—CF₂CF₃ and CH₃.

[0016] Preferably R¹ represents —(CO)_(x)C₁₋₅alkyl or —(CO)_(x)C₁₋₅fluoroalkyl, which fluoroalkyl moiety contains at least 1 fluorine atomand not more than 3 consecutive perfluorocarbon atoms, more preferablyC₁₋₃alkyl optionally substituted by up to 3 fluorine atoms. Mostpreferably R¹ represents, —C₁₋₃alkyl (e.g. methyl, ethyl, propyl orisopropyl), —CHF₂, —CF₃, or —CH₂CF₃, more preferably —CH₃, —CF₃ or—CH₂CF₃, especially —CH₃. We also most prefer R¹ to represent —CH₂CF₂CF₃or —CF₂CF₃. We especially prefer R¹ to represent —CF₂CF₃ or —CH₂CF₃,particularly —CH₂CF₃.

[0017] Another group of compounds of particular interest are those inwhich R¹ represents C₁₋₃ fluoroalkylC₀₋₆alkylene—, particularly—(CH₂)₃CF₂CF₃, —CH₂CF₂CF₃ or —CH₂CF₃.

[0018] Preferably R² and R³ independently represent methyl or hydrogen,more preferably hydrogen.

[0019] Suitable salts include alkali metal salts such as sodium andpotassium and tertiary alkyl ammonium salts such as tert-butyl ammonium.

[0020] Preferably compounds of formula (I) will be present as the freeacid.

[0021] It will be understood that for N greater than 1, th position ofR² and R³ in each repeating unit need not necessarily be the same, egthey may perhaps be rev rsed. Nevertheless it is preferred that therespective positions ar the same for each repeating unit.

[0022] Compounds of formula (I) may contain one or more chiral centres.It will be understood that compounds of formula (I) include all opticalisomers of the compounds of formula (I) and mixtures thereof, includingracemic mixtures thereof.

[0023] In a further aspect the invention provides a pharmaceuticalaerosol formulation which comprises particulate medicament, afluorocarbon or hydrogen-containing chlorofluorocarbon propellant, ormixtures thereof, and a compound of formula (I) as described above.

[0024] The compounds of formula (I) employed for the preparation offormulations according to the present invention are effective suspensionstabilisers at low concentrations relative to the amount of medicament.Thus, the amount of compound of formula (I) employed is desirably in therange of 0.05% to 20% w/w, particularly 0.5% to 10% w/w, moreparticularly 0.5% to 5% w/w, relative to the medicament.

[0025] The particle size of the particulate (e.g. micronised) medicamentshould be such as to permit inhalation of substantially all of themedicament into the lungs or nasal cavity upon administration of theaerosol formulation and will thus be less than 100 microns, desirablyless than 20 microns, and preferably will have a mass median aerodynamicdiameter (MMAD) in the range 1-10 microns, e.g. 1-5 microns.

[0026] The final aerosol formulation desirably contains 0.005-10% w/w,preferably 0.005-5% w/w, especially 0.01-1.0% w/w, of medicamentrelative to the total weight of the formulation.

[0027] Medicaments which may be administered in aerosol formulationsaccording to the invention include any drug useful in inhalation therapyand which may be presented in a form which is substantially completelyinsoluble in the selected propellant. Appropriate medicaments may thusbe selected from, for example, analgesics, e.g., codeine,dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations,e.g., diltiazem; antiallergics, e.g., cromoglycate (e.g. as sodiumsalt), ketotifen or nedocromil (e.g. as sodium salt); anti-infectivese.g. cephalosporins, penicillins, streptomycin, sulphonamides,tetracyclines and pentamidine; anti-histamines, e.g. methapyrilene;anti-inflammatories, e.g. beclomethasone (e.g. as dipropionate),fluticasone (e.g. as propionate), flunisolide, budesonide, rofleponide,mometasone furoate, ciclesonide, triamcinolone acetonide or 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17αpropionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester; anti-tussives, e.g.noscapine; bronchodilators, e.g. albuterol (e.g. as free base orsulphate), salmeterol (e.g. as xinafoate), ephedrine, adrenaline,fenoterol (e.g. as hydrobromide), formoterol (e.g. as fumarate),isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine,pirbuterol (e.g. as acetate), reproterol (e.g. as hydrochloride),rimiterol, terbutaline (e.g. as sulphate), isoetharine, tulobuterol,4-hydroxy-7-[2-[[2-[[3-(2-phenylethoxy)pro-pyl]sulfonyl]ethyl]amino]ethyl-2(3H)-benzothiazolone;diuretics, e.g. amiloride; anticholinergics, .g., ipratropium (e.g. asbromide), tiotropium, atropine or oxitropium; hormones, e.g. cortisone,hydrocortisone or prednisolone; xanthines, e.g. aminophylline, cholinetheophyllinate, lysine theophyllinate or theophylline; therapeuticproteins and peptides, e.g. insulin or glucagon. It will be clear to aperson skilled in the art that, where appropriate, the medicaments maybe used in the form of salts, (e.g., as alkali metal or amine salts oras acid addition salts) or as esters (e.g. lower alkyl esters) or assolvates (e.g. hydrates) to optimise the activity and/or stability ofthe medicament and/or to minimise the solubility of the medicament inthe propellant. It will be further clear to a person skilled in the artthat where appropriate the medicaments may be used in the form of a pureisomer, for example, R-albuterol or RR-formoterol.

[0028] Particularly preferred medicaments for administration usingaerosol formulations in accordance with the invention includeanti-allergics, bronchodilators and antiinflammatory steroids of use inthe treatment of respiratory disorders such as asthma, COPD or rhinitisby inhalation therapy, for example, cromoglycate (e.g. as sodium salt),albuterol (e.g. as free base or the sulphate), salmeterol (e.g. asxinafoate), formoterol (e.g. as fumarate), terbutaline (e.g. assulphate), reproterol (e.g. as hydrochloride), a beclomethasone ester(e.g. as dipropionate), a fluticasone ester (e.g. as propionate).Salmeterol, especially salmeterol xinafoate, albuterol sulphate,fluticasone propionate, beclomethasone dipropionate and physiologicallyacceptable salts and solvates thereof are especially preferred.

[0029] It will be appreciated by those skilled in the art that theaerosol formulations according to the invention may, if desired, containa combination of two or more active ingredients. Thus suitablecombinations include bronchodilators (e.g. albuterol or isoprenaline) incombination with an anti-inflammatory steroid (e.g. beclomethasoneester); a bronchodilator in combination with an anti-allergic (e.g.cromoglycate). Exemplary combinations also include: ephedrine andtheophylline; fenoterol and ipratropium (e.g. as bromide); isoetharineand phenylephrine; albuterol (e.g. as free base or as sulphate) andbeclomethasone ester (e.g. as dipropionate); budesonide and formoterol(e.g. as fumarate) which is of particular interest; and salmeterol(particularly as salmeterol xinafoate) and fluticasone ester (e.g. aspropionate) also of particular interest.

[0030] The propellants for use in the invention may be any fluorocarbonor hydrogen-containing chlorofluorocarbon or mixtures thereof having asufficient vapour pressure to render them effective as propellants.Preferably the propellant will be a non-solvent for the medicament.Suitable propellants include, for example, C₁₋₄hydrogen-containingchlorofluorocarbons such as CH₂ClF, CClF₂CHClF, CF₃CHClF, CHF₂CClF₂,CHClFCHF₂, CF₃CH₂Cl and CClF₂CH₃; C₁₋₄hydrogen-containing fluorocarbonssuch as CHF₂CHF₂, CF₃CH₂F, CHF₂CH₃ and CF₃CHFCF₃; and perfluorocarbonssuch as CF₃CF₃ and CF₃CF₂CF₃.

[0031] Where mixtures of the fluorocarbons or hydrogen-containingchlorofluorocarbons are employed they may be mixtures of the aboveidentified compounds, preferably binary mixtures, with otherfluorocarbons or hydrogen-containing chlorofluorocarbons for exampleCHClF₂, CH₂F₂ and CF₃CH₃. Particularly preferred as propellants areC₁₋₄hydrogen-containing fluorocarbons such as 1,1,1,2-tetrafluoroethan(CF₃CH₂F) and 1,1,1,2,3,3,3-heptafluoro-n-propane (CF₃CHFCF₃) ormixtures thereof. Preferably a single fluorocarbon orhydrogen-containing chlorofluorocarbon is employed as the propellant,for example, 1,1,1,2-tetrafluoroethane (HFA 134a) or1,1,1,2,3,3,3heptafluoro-n-propane (HFA 227), especially1,1,1,2-tetrafluoroethane.

[0032] It is desirable that the formulations of the invention contain nocomponents which may provoke the degradation of stratospheric ozone. Inparticular it is desirable that the formulations are substantially freeof chlorofluorocarbons such as CCl₃F, CCl₂F₂ and CF₃CCl₃.

[0033] If desired the propellant may additionally contain a volatileadjuvant such as a saturated hydrocarbon, for example, propane,n-butane, isobutane, pentane and isopentane or a dialkyl ether, forexample, dimethyl ether. In general, up to 50% w/w of the propellant maycomprise a volatile hydrocarbon, for example 1 to 30% w/w. However,formulations which are substantially free of volatile adjuvants arepreferred. In certain cases, it may be desirable to include appropriateamounts of water, which can be advantageous in modifying the dielectricproperties of the propellant.

[0034] Polar adjuvants which may if desired, be incorporated into theformulations according to the present invention include, for example,C₂₋₆aliphatic alcohols and polyols such as ethanol, isopropanol andpropylene glycol and mixtures thereof. Preferably ethanol will beemployed. In general only small quantities (e.g. 0.05 to 3.0% w/w) ofpolar adjuvants are required and the use of quantities in excess of 5%w/w may disadvantageously tend to dissolve the medicament. Formulationspreferably contain less than 1% w/w, for example, about 0.1% w/w ofpolar adjuvant. Polarity may be determined, for example, by the methoddescribed in European Patent Application Publication No. 0327777.

[0035] However as the compounds of formula (I) are adequately soluble inthe fluorocarbon or hydrogen-containing chlorofluorocarbon propellantthe need to use a polar adjuvant is obviated. This is advantageous aspolar adjuvants especially ethanol are not suitable for use with allpatient groups. Formulations containing a compound of formula (I) whichavoid use of a polar adjuvant are preferred.

[0036] In addition to one or more compounds of the general formula (I),the formulations according to the present invention may optionallycontain one or more further ingredients conventionally used in the artof pharmaceutical aerosol formulation. Such optional ingredientsinclude, but are not limited to, taste masking agents, sugars, buffers,antioxidants, water and chemical stabilisers.

[0037] A particularly preferred embodiment of the invention provides apharmaceutical aerosol formulation consisting essentially of one or moreparticulate medicament(s), one or more fluorocarbon orhydrogen-containing chlorofluorocarbon propellant(s) and one or morecompound(s) of formula (I).

[0038] A further embodiment of the invention is a s aled containercapable of withstanding the pressure required to maintain the propellantas a liquid, such as a metered dose inhaler, containing therein theaerosol formulation as described above.

[0039] The term “metered dose inhaler” or MDI means a unit comprising acan, a secured cap covering the can and a formulation metering valvesituated in the cap. MDI system includes a suitable channeling device.Suitable channeling devices comprise for example, a valve actuator and acylindrical or cone-like passage through which medicament may bedelivered from the filled canister via the metering valve to the nose ormouth of a patient such as a mouthpiece actuator.

[0040] As an aspect of this invention there are also provided processesfor the preparation of compounds of formula (I).

[0041] Therefore a process for preparing a compound of formula (I) isprovided which comprises:

[0042] (a) reacting a compound of formula (II)

[0043] wherein n is defined above and L¹ is a leaving group or aprotected derivative thereof, with a compound of formula (III)

[0044] wherein N, R¹, R² and R³ are defined above; or

[0045] (b) reacting a compound of formula (IV)

[0046] wherein n is defined above, or a protected derivative thereof,with a compound of formula (V)

[0047] wherein N, R¹, R² and R³ are defined above and L² is a leavinggroup; or

[0048] (c) reacting a compound of formula (VI)

[0049] wherein n, N, R² and R³ are defined above, or a protectedderivative thereof, with a compound of formula (VII)

[0050] wherein R¹ is defined above and L³ is a leaving group; or

[0051] (d) reacting a compound of formula (VIII)

[0052] wherein n, N, R² and R³ are defined above and L⁴ is a leavinggroup with a compound of formula (IX)

[0053] wherein R¹ is defined above; or

[0054] (e) oxidising a compound of formula (X)

[0055] wherein n, N, R¹, R² and R³ are defined above, to give thecorresponding acid or a salt or solvate thereof; or

[0056] (f) deprotecting a protected compound of formula (I).

[0057] A further process for preparing a compound of formula (I) isprovided which comprises:

[0058] (g) preparing a compound of formula (I) wherein x is 1 byreacting a compound of formula (VI) as defined above, or a derivativethereof wherein the carboxylic acid group is protected, with an acid offormula (XI)

[0059] or a salt or solvate thereof or a derivative thereof (such as ananhydride including a mixed anhydride or an acid chloride) wh rein R⁴represents —C₁₋₉ alkyl or a —C₁₋₉ fluoroalkyl moiety which contains atleast 1 fluorine atom and not more than 3 consecutive perfluorocarbonatoms; or

[0060] (h) preparing a compound of formula (I) wherein x is 1 byreacting a compound of formula (VIII) as defined above or a protectedderivative thereof wherein the carboxylic acid group is protected withan acid of formula (XI) or a salt or solvate thereof.

[0061] In process (a), (b), (c) and (d) the carboxylic acid ispreferably protected for example, as an ester such as a C₁₋₄alkyl esteror a benzyl ester. The process above will usually be performed in thepresence of a strong non-nucleophilic base, for example, tert-butoxidesuch as potassium tert-butoxide or lithium diisopropylamine in an inertsolvent, for example, toluene or dimethylformamide (DMF), attemperatures in the range 0 to reflux.

[0062] Preferably potassium tert-butoxide will be used as the base andtoluene will be used as the solvent, preferably at reflux. Suitableleaving groups L¹ L², L³ and L⁴ include halogen, especially bromine.

[0063] In process (e) methods for oxidising a primary alcohol to thecorresponding carboxylic acid, using strong oxidising agents are wellknown to persons skilled in the art. Suitable reagents include: chromicacid, permanganate, for example, potassium permanganate, and nitricacid. Permanganate is preferred for use in process (e), especiallypotassium permanganate.

[0064] In process (f), examples of protecting groups (e.g. forcarboxylic acids) and means for their removal can be found in“Protecting Groups In Organic Synthesis” by Theodora Green and Peter G.M Wuts (John Wiley and Sons Inc 1999). Suitable carboxylic acidprotecting groups include but are not limited to carboxylic acid esters,for example, ethyl ester, aryl esters e.g. benzyl ester.

[0065] Protecting groups can be removed by acid or base catalysedhydrolysis or reduction for example, by hydrogenation. Where thecarboxylic acid is protected as the benzyl ester, the protecting groupmay be removed for example by hydrogenation. Where the carboxylic acidis protected as the C₁₋₄alkyl ester, the protecting group may be removedfor example by base hydrolysis.

[0066] Methods of esterifying acids are well know to person skilled inthe art. Process (g) may be performed in an inert solvent at anon-extreme temperature under acidic conditions. Preferably thecarboxylic acid moiety in the compound of formula (VI) will be protectede.g with a group mentioned above in relation to process (f). Thereaction may be encouraged to be more efficient by, for example, thepresence of a water scavenger such magnesium sulphate or molecularsieves.

[0067] Process (h) may be performed in an inert solvent at a non-extremetemperature in the presence of a sterically hindered or non-nucleophilicbase, for example, triethylamine or Hunig's base. Preferably thecarboxylic acid moiety in the compound of formula (VIII) will beprotected.

[0068] Compounds of formula (VI) may be prepared by a processcomprising:

[0069] (i) reacting a compound of formula (IV) as defined above, or aprotected derivative thereof, with a compound of formula (XII)

[0070] wherein N, R² and R³ are as defined above and L⁵ is a leavinggroup (such as one mentioned above), or a protected derivative thereof;or

[0071] (ii) reacting a compound of formula (II) as defined above, or aprotected derivative thereof, with a compound of formula (XIII)

[0072] wherein N, R² and R³ are as defined above, or a derivativethereof wherein the non-reacting hydroxyl is protected.

[0073] Compounds of formula (VIII) may be prepared by a processcomprising:

[0074] (i) reacting a compound of formula (IV) as defined above, or aprotected derivative thereof, with a compound of formula (XIV)

[0075] wherein N, R² and R³ are as defined above, L⁶ is a potentialleaving group and L⁷ is a leaving group; or

[0076] (ii) reacting a compound of formula (II) as defined above, or aprotected derivative thereof, with a compound of formula (XV)

[0077] wherein N, R² and R³ are as defined above and L⁸ is a potentialleaving group.

[0078] L⁶ and L⁸ are potential leaving groups which may, for example, beprotected hydroxyl groups which can be selectively deprotected andconverted into good leaving groups by treatment with a halogenatingagent such as carbon tetrabromide and triphenylphosphine or phosphoruspentachloride or by treatment with methane sulphonyl chloride orparatoluene sulphonyl chloride to give a compound of formula (VIII).

[0079] Compounds of formula (X) may be prepared by a process comprising:

[0080] (i) reacting a compound of formula (XVI)

[0081] wherein n is defined above and L⁹ is a leaving group (such as onementioned above) or a derivative wherein the hydroxyl is protected, witha compound of formula (III) as defined above; or

[0082] (ii) reacting a compound of formula (XVII)

[0083] wherein n is defined above, or a derivative thereof wherein thenon-reacting hydroxyl is protected, with a compound of formula (V) asdefined above.

[0084] Steps (i) and (ii) in the preparation of compounds of formula(VI), (VIII) and (X) may be performed under condition analogous to thosedescribed above for processes (a), (b), (c) and (d) above.

[0085] Compounds of formula (XI) may be prepared by oxidising a compoundof formula (XVIII)

[0086] wherein R⁴ is as defined above.

[0087] Suitable conditions include those described above for process(e).

[0088] Compounds of formula (VII), (IX), (XI), (XVI), (XVII) and (XVIII)are known or can be prepared by known methods.

[0089] Compounds of formula (II), (III), (IV), (V), (XII), (XIII), (XIV)and (XV) may be prepared by methods analogous to those described aboveor by known methods.

[0090] It will be clear to a person skilled in the art that an oxiranesuch as ethylene oxide or propylene oxide may be used to build up anumber of ether monomer units especially where the units havesubstituents R² and R³ independently selected from hydrogen and m thyl.

[0091] Certain compounds of formula (III), (V), (VI), (VII), (X), (XII)(XIII), (XIV) and (XV) are new and form an aspect of the invention.

[0092] In addition processes for preparing formulations including one ormore compounds of formula (I) form an aspect of this invention.

[0093] The formulations of the invention may be prepared by dispersal ofthe medicament and a compound of formula (I) in the selected propellantin an appropriate container, for example, with the aid of sonication ora high-shear mixer. The process is desirably carried out undercontrolled humidity conditions.

[0094] The chemical and physical stability and the pharmaceuticalacceptability of the aerosol formulations according to the invention maybe determined by techniques well known to those skilled in the art.Thus, for example, the chemical stability of the components may bedetermined by HPLC assay, for example, after prolonged storage of theproduct. Physical stability data may be gained from other conventionalanalytical techniques such as, for example, by leak testing, by valvedelivery assay (average shot weights per actuation), by dosereproducibility assay (active ingredient per actuation) and spraydistribution analysis.

[0095] The suspension stability of the aerosol formulations according tothe invention may be measured by conventional techniques, for example,by measuring flocculation size distribution using a back lightscattering instrument or by measuring particle size distribution bycascade impaction or by the “twin impinger” analytical process. As usedherein reference to the “twin impinger” assay means “Determination ofthe deposition of the, emitted dose in pressurised inhalations usingapparatus A” as defined in British Pharmacopaeia 1988, pages A204-207,Appendix XVII C. Such techniques enable the “respirable fraction” of theaerosol formulations to be calculated. One method used to calculate the“respirable fraction” is by reference to “fine particle fraction” whichis the amount of active ingredient collected in the lower impingementchamber per actuation expressed as a percentage of the total amount ofactive ingredient delivered per actuation using the twin impinger methoddescribed above.

[0096] MDI canisters generally comprise a container capable ofwithstanding the vapour pressure of the propellant used such as aplastic or plastic-coated glass bottle or preferably a metal can, forexample, aluminium or an alloy thereof which may optionally be anodised,lacquer-coated and/or plastic-coated (e.g. incorporated herein byreference WO96/32099 wherein part or all of the internal surfaces arecoated with one or more fluorocarbon polymers optionally in combinationwith one or more non-fluorocarbon polymers), which container is closedwith a metering valve. The cap may be secured onto the can viaultrasonic welding, screw fitting or crimping. MDIs taught herein may beprepared by methods of the art (e.g., see Byron, above and WO/96/32099).Preferably the canister is fitted with a cap assembly, wherein a drugmetering valve is situated in the cap, and said cap is crimped in place.

[0097] The m tering valves are designed to deliver a metered amount ofthe formulation per actuation and incorporate a gasket to prevent lakage of propellant through the valve. The gasket may comprise anysuitable elastomeric material such as, for example, low densitypolyethylene, chlorobutyl, black and white butadiene-acrylonitrilerubbers, butyl rubber and neoprene. Suitable valves are commerciallyavailable from manufacturers well known in the aerosol industry, forexample, from Valois, France (e.g. DF10, DF30, DF60), Bespak plc, UK(e.g. BK300, BK357) and 3M-Neotechnic Ltd, UK (e.g. Spraymiser™).

[0098] A further aspect of this invention comprises a process forfilling the said formulation into MDIs.

[0099] Conventional bulk manufacturing methods and machinery well knownto those skilled in the art of pharmaceutical aerosol manufacture may beemployed for the preparation of large scale batches for the commercialproduction of filled canisters. Thus, for example, in one bulkmanufacturing method a metering valve is crimped onto an aluminium canto form an empty canister. The particulate medicament is added to acharge vessel and liquified propellant is pressure filled through thecharge vessel into a manufacturing vessel, together with liquifiedpropellant containing the surfactant. The drug suspension is mixedbefore recirculation to a filling machine and an aliquot of the drugsuspension is then filled through the metering valve into the canister.

[0100] In an alternative process, an aliquot of the liquifiedformulation is added to an open canister under conditions which aresufficiently cold to ensure formulation does not vaporise, and then ametering valve crimped onto the canister.

[0101] Typically, in batches prepared for pharmaceutical use, eachfilled canister is check-weighed, coded with a batch number and packedinto a tray for storage before release testing.

[0102] Each filled canister is conveniently fitted into a suitablechanneling device prior to use to form a metered dose inhaler system foradministration of the medicament into the lungs or nasal cavity of apatient. Metered dose inhalers are designed to deliver a fixed unitdosage of medicament per actuation or “puff”, for example, in the rangeof 10 to 5000 micrograms of medicament per puff.

[0103] Administration of medicament may be indicated for the treatmentof mild, moderate, severe acute or chronic symptoms or for prophylactictreatment. It will be appreciated that the precise dose administeredwill depend on the age and condition of the patient, the particularparticulate medicament used and the frequency of administration and willultimately be at the discretion of the attendant physician. Whencombinations of medicaments are employed the dose of each component ofthe combination will in general be that employed for each component whenused alone. Typically, administration may be one or more times, forexample, from 1 to 8 times per day, giving for example 1, 2, 3 or 4puffs each time.

[0104] Suitable daily doses, may be, for example, in the range 50 to 200micrograms of salmeterol, 100 to 1000 micrograms of albuterol, 50 to2000 micrograms of fluticasone propionate or 100 to 2000 micrograms ofbeclomethasone dipropionate, depending on the severity of the disease.

[0105] Thus, for example, each valve actuation may deliver 25 microgramsof salmeterol, 100 micrograms of albuterol, 25, 50, 125 or 250micrograms of fluticasone propionate or 50, 100, 200 or 250 microgramsof beclomethasone dipropionate. Dos s for Seretide™, which is acombination of salmeterol (eg as xinafoate salt) and fluticasonepropionate, will usually be those given for the corresponding individualcomponent drugs. Typically each filled canister for use in a metereddose inhaler contains 60, 100, 120, 160 or 240 metered doses or puffs ofmedicament.

[0106] An appropriate dosing regime for other medicaments will be knowor readily available to persons skilled in the art.

[0107] The use of the compounds of formula (I) as described aboveespecially in the preparation of a pharmaceutical formulation; use of aformulation as described above in inhalation therapy, for example, forthe treatment or prophylaxis of respiratory disorders; and use of ametered dose inhaler system in the treatment or prophylaxis ofrespiratory disorders are all alternative aspects of this invention.

[0108] A still further aspect of the present invention comprises amethod of treating respiratory disorders such as, for example, asthma,which comprises administration by inhalation of an effective amount of aformulation as herein described.

[0109] The following non-limiting examples serve to illustrate theinvention.

EXAMPLES

[0110] The mass spectra were recorded on a HP5989A Engine MassSpectrometer using thermospray positive ion mode.

[0111] The solvent system used for TLC was 10% methanol/1% ammonia indichloromethane. Where organic solutions were dried during work upmagnesium sulphate was used unless specified otherwise.

[0112] LCMS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm×4.6mm ID) eluting with 0.1% HCO₂H and 0.01M ammonium acetate in water(solvent A), and 0.05% HCO₂H and 5% water in acetonitrile (solvent B),using the following elution gradient 0-0.7 min 0% B, 0.7-4.2 min 0-100%B, 4.2-5.3 min 100% B, 5.3-5.5 min 100-0% B at a flow rate of 3 mL/min.

[0113] GC was conducted on a methyl silicone column 25 m×0.25 mm×0.25 umHP1 or equivalent. The carrier gas was helium at a flow rate of 1mL/min. The injection volume was 1 μL and the injector temperature was250° C. with a split injection ratio of 50:1. The septum purge was 2mL/min. Oven temperature program: initial temperature 150° C. ramp at10° C./min to 300° C. then hold at 300° C. for 30 mins. The flameionisation detector was at 300° C. with nitrogen make up gas at 30mL/min.

Example 1

[0114] 2,5,8,11-Tetraoxatridecan-13-oic acid

[0115] (a) Ethyl 2,5,8,11-tetraoxatridecan-13-oate

[0116] To a stirred solution of triethyl glycol monomethyl ether (3 g)in toluene (100 mL) was added potassium tert-butoxide (2.88 g) and thereaction was stirred at 20° C. for 30 minutes. Ethyl bromoacetate (4.05g) was added and th reaction was heated at reflux for 19 hours. Thereaction was cooled to 20° C. and the solvent was removed in vacuo.

[0117] The residue was partitioned between water (200 mL) anddichloromethane (200 mL). The organic layer was dried and the solventwas removed in vacuo. Purification by chromatography on silica gel(Biotage), eluting with 50% ethyl acetate in cyclohexane gave the titlecompound as a clear oil (1.5 g). Mass spectrum 268 m/z [MNH₄ ^(+])

[0118] (b) 2,5,8,11-Tetraoxatridecan-13-oic acid

[0119] The product of step (a) (1.5 g) was stirred in a sodium hydroxidesolution (0.1 M, 30 mL) for 5 hours. The reaction mixture was adjustedto pH 2 by the addition of hydrochloric acid (2 M) and then diluted withbrine (300 mL). This was extracted with dichloromethane (2×300 mL) andthe combined organic layers were dried and the solvent was removed invacuo. Purification by chromatography on silica gel (Biotage), elutingwith 10% methanol in dichloromethane gave the title compound as a clearoil (900 mg).

[0120] Mass spectrum 240 m/z [MNH₄ ⁺] R_(f)0.15

[0121] Other compounds which may be prepared by methods analogous tothose given for Example 1 above:

Example 2

[0122] 2,5,8,11,14,17,20-Heptaoxadocosan-22-oic acid

[0123] Clear oil. Mass spectrum 372 m/z [MNH₄ ⁺] R_(f)0.28

Example 3

[0124] 2,5,8,11-Tetraoxahexadecan-16-oic acid

[0125] Clear oil. Mass spectrum 282 m/z [MNH₄ ⁺] R_(f) 0.35

Example 4

[0126] 2,5,8,11,14,17,20-Heptaoxapentacosan-25-oic acid

[0127] Clear oil. Mass spectrum 414 m/z [MNH₄ ⁺] R_(f)0.25

Example 5

[0128] 23,23,23-Trifluoro-3,6,9,12,15,18,21-heptaoxatricosan-1-oic acid

[0129] (a) 1-Phenyl-2,5,8, 11,14,17-hexaoxanonadecan-19-ol

[0130] To a stirred suspension of sodium hydride (50% dispersion inmineral oil, 2.55 g) in tetrahydrofuran (100 mL) was added hexaethyleneglycol (25 g). The reaction mixture was stirred at 5-15° C. for 10minutes, then benzyl bromide (16.66 g) was added. The suspension wasallowed to stand at 20° C. for 72 hours then the reaction mixture wasdiluted with water (250 mL) and extracted with cyclohexane (250+125 mL).Aqueous sodium chloride solution (15% w/w, 300 mL) was added to theaqueous phase and the resulting solution was extracted with ethylacetate (3×250 mL). The combined ethyl acetate extracts wereconcentrated in vacuo to give the title compound as an orange oil (18.68g). LC retention time 2.50 mins. Mass spectrum m/z 390 [MNH₄ ⁺]

[0131] (b) 19-Phenyl-3,6,9, 12,15,18-hexaoxanonadec-1-yl4-methylbenzenesulfonate

[0132] To a stirred solution of the product of step (a) (1 g) indichloromethane (20 mL), ρ-toluenesulfonyl chloride (0.66 g) andtriethylamine (0.5 mL) were added and the reaction was stirred at 20° C.for 24 hours. The reaction mixture was diluted with dichloromethane (100mL) then washed with water (100 mL) and brine (100 mL), dried and thesolvent removed in vacuo. Purification by column chromatography onsilica gel (Biotage), eluting with 10% ethyl acetate in cyclohexane togive the title compound (1 g).

[0133] LC retention time 3.37 mins. Mass spectrum m/z 544 [MNH₄ ⁺]

[0134] (c)22,22,22-Trifluoro-1-phenyl-2,5,8,11,14,17,20-heptaoxadocosane

[0135] To a stirred solution of trifluoroethanol (0.1 g) and sodiumhydride (60% dispersion in mineral oil, 0.05 g) in tetrahydrofuran (10mL) was added the product of step (b) (0.5 g) and the reaction wasstirred for 24 hours at 20° C. The reaction was quenched by the additionof methanol (5 mL) and the solvent was removed in vacuo. The residue waspartitioned between ethyl acetate (50 mL) and water (50 mL). The organiclayer was washed with brine (50 mL), dried and the solvent removed invacuo. Purification by column chromatography on silica gel (Biotage),eluting with 50% ethyl acetate in cyclohexane to give the title compound(0.27 g). LC retention time 3.17 mins

[0136] Mass spectrum m/z 472 [MNH₄ ⁺]

[0137] (d) 20,20,20-Trifluoro-3,6,9,12,15,18-hexaoxaicosan-1-ol

[0138] A stirred solution of the product of step (c) (16 g) and 10%palladium on carbon (1 g) in acetic acid:ethanol (1:1, 150 mL) wasplaced under an atmosphere of hydrogen at 20° C. for 24 hours. Thereaction mixture was filtered through a pad of celite and the solventwas removed in vacuo to give the title compound (11 g).

[0139] Mass spectrum m/z 382 [MNH₄ ⁺]

[0140] (e) Ethyl23,23,23-trifluoro-3,6,9,12,15,18,21-heptaoxatricosan-1-oate

[0141] To a stirred solution of the product of step (d) (1.5 g) intoluene (30 mL) was added potassium tert-butoxide (0.69 g) and theresulting mixture was stirred at room temperature for 3 hours. Ethylbromoacetate (1.38 g) was added and the reaction was stirred at 130° C.for 48 hours. The solvent was removed in vacuo and the residue wasdissolved in dichloromethane (500 mL) and washed with water (2×400 mL).The organic layer was washed with brine (300 mL), dried and the solventwas removed in vacuo. The residue was purified by column chromatographyon silica gel (Biotage), eluting with 65-75% ethyl acetate incyclohexane to give the title compound as a brown oil (0.40 g).

[0142] LC retention time 2.77 min. Mass spectrum m/z 468 [MNH₄ ⁺]

[0143] (f) 23,23,23-Trifluoro-3,6,9,12,15,18,21-heptaoxatricosan-1-oicacid

[0144] The product of step (e) (400 mg) was dissolved in an aqueoussodium hydroxide solution (0.1 M, 10 mL) and the reaction was stirred at20° C. for 16 hours. The reaction mixture was acidified to pH 2 by theaddition of hydrochloric acid (2 M), then this was diluted with brine(200 mL) and extracted with dichloromethane (2×200 mL). The combinedorganic layers were dried and the solvent was removed in vacuo to givethe title compound as a colourless oil (330 mg). LC retention time 2.41mins. Mass spectrum m/z 440 [MNH₄ ⁺]

Example 6

[0145] {[2-({2-[(2,2,2-Trifluoroethyl)oxy]ethyl}oxy)ethyl]oxy}aceticacid

[0146] The compound was made by an analogous method to Example 5.

[0147] Clear oil. LC retention time 2.15 mins. Mass spectrum m/z 245(M⁺]

Example 7

[0148] 2,5,8,11,14,17,20,23,26,29-Decaoxahentriacontan-31-oic acid

[0149] (a) 2-[2-(2-Methoxyethoxy)ethoxy]ethyl 4-methylbenzenesulfonate

[0150] A solution of triethylene glycol monomethyl ether (300 g) intetrahydrofuran (550 mL) was added dropwise over 105 minutes to astirred aqueous sodium hydroxide solution (2 M, 1.28 L) at 0-5° C. Asolution of ρtoluenesulphonyl chloride (383 g) in tetrahydrofuran (600mL) was then added to the reaction mixture over 150 minutes, maintainingthe temperature at 0-9° C. The reaction mixture was stirred at 0-5° C.for a further 2 hours and then allowed to warm to 20° C. and stirred for16 hours. Additional aqueous sodium hydroxide solution (2 M, 90 mL) wasthen added slowly to the reaction mixture and stirring was continued fora further 1 hour. Water (1 L) was added to the reaction mixture whichwas then extracted with toluene (2×1.8 L). The combined organic extractswere washed with water (3×1.8 L) and then concentrated in vacuo to givethe title compound as a colourless oil (448 g). GC retention time 11.2mins

[0151] (b) 1-Phenyl-2,5,8,11,14,17-hexaoxanonadecan-19-ol

[0152] To a stirred mixture of hexaethylene glycol (10 g), benzylbromide (4.53 mL) and diisopropyl ether (25 mL) was addedtetrahydrofuran (10 mL). The mixture was cooled to 15-20° C. and aqueoussodium hydroxide (10.8 M, 4.92 mL) was added slowly maintaining thetemperature at 15-20° C. during addition. The resulting mixture wasallowed to warm to 20° C. and stirred for a further 17 hours. Water (50mL) was then added to the reaction mixture, which was then washed withdiisopropyl ether (25 mL). Sodium chloride (10 g) was added to theaqueous phase which was extracted with ethyl acetate (3×25 mL). Thecombined ethyl acetate extracts were dried (Na₂SO₄) and concentrated invacuo to give the title compound as a mobile oil (6.29 g). GC retentiontime 14.2 mins

[0153] (c) 1-Phenyl-2,5,8,11,14,17,20,23,26,29-decaoxatriacontane

[0154] To a stirred solution of the product of step (b) (25 g) intetrahydrofuran (500 mL) at −20° C. was added a solution of potassiumtert-butoxide in tetrahydrofuran (1.61 M, 50 mL) over 1 hour,maintaining the temperature at about −20° C. The reaction mixture wasstirred for a further 15 minutes then a solution of the product of step(a) (29.7 g) in tetrahydrofuran (100 mL) was added over 90 minutes,maintaining the temperature at about −20° C. After stirring at −20° C.for a further 3 hours, the mixture was allowed to warm to 20° C. andstirred for 16 hours. Water (125 mL) was then added and the resultantmixture was concentrated in vacuo to 140 mL. Sodium chloride (12.5 g)was added to the stirred concentrate, which was then washed withdiisopropyl ether (4×125 mL). The aqueous phase was diluted with water(50 mL) and extracted with dichloromethane (3×125 mL). The combineddichloromethane extracts were concentrated in vacuo to give the titlecompound as an orange-brown oil (27.93 g).

[0155] GC retention time 21.8 mins

[0156] (d) 2,5,8,11,14,17,20,23,26-Nonaoxaoctacosan-28-ol

[0157] A solution of product from step (c) (13.56 g) in ethyl acetate(68 mL) was stirred under a hydrogen atmosphere with 5% palladium oncarbon (1.36 g, wet paste) for 3 hours. The catalyst was then removed byfiltration and the filtrate was concentrated in vacuo to give the titlecompound as a pale yellow oil (10.93 g). GC retention time 15.2 mins

[0158] (e) 2,5,8,11,14,17,20,23,26,29-Decaoxahentriacontan-31-oic acid

[0159] To a stirred solution of the product of step (d) (20 g) in drytetrahydrofuran (500 mL) at 0° C. was added sodium hydride (60%dispersion in mineral oil, 2.43 g) portionwise. The reaction was stirredat 0° C. for 30 minutes then ethyl bromoacetate (8.19 g) was addeddropwise and the reaction was allowed to warm to 20° C. and stirred fora further 3 hours. Ethanol (100 mL) was then added and stirring wascontinued at 20° C. for 30 minutes. Sodium hydroxide solution (2M, 100mL) was then added and the resulting mixture was stirred at 20° C. for 2hours. The reaction mixture was then partitioned between dichloromethane(700 mL) and water (700 mL). The aqueous layer was acidified to pH 1 bythe addition of hydrochloric acid (2 M) and then extracted withdichloromethane (3×500 mL). The combined organic layers were dried andthe solvent removed in vacuo. Purification by chromatography on silicagel (Biotage), eluting with 10% methanol/1% ammonia (specific gravity0.880) in dichloromethane gave the title compound as a pale yellow oil(15 g). LC retention time 2.18 mins. Mass spectrum m/z 485 [M⁺]

Example 8

[0160]25,25,26,26,26-Pentafluoro-3,6,9,12,15,18,21-heptaoxahexacosan-1-oicacid

[0161] Prepared by a method analogous to Example 5.

[0162] Pale yellow oil. LC retention time 2.92 mins. Mass spectrum m/z518 [MNH₄ ⁺]

Example 9

[0163] (2-{2-[(4,4,5,5,5-Pentafluoropentyl)oxy]ethoxy}ethoxy)acetic acid

[0164] Prepared by a method analogous to Example 5

[0165] Pale yellow oil. LC retention time 2.85 mins. Mass spectrum m/z323 [M⁺]

Example 10

[0166] {2-[2-(2,2,3,3,3-Pentafluoropropoxy)ethoxy]ethoxy}acetic acid

[0167] Prepared by a method analogous to Example 5

[0168] Pale yellow oil. LC retention time 2.64 mins. Mass spectrum m/z295 [M⁺]

Example 11

[0169]23,23,24,24,24-Pentafluoro-3,6,9,12,15,18,21-heptaoxatetracosan-1-oicacid

[0170] Prepared by a method analogous to Example 5

[0171] Pale yellow oil. LC retention time 2.77 mins. Mass spectrum m/z471 [M⁺]layers were washed with water (20 mL) and concentrated in vacuo.Purification by chromatography on silica gel (Biotage), eluting with1.5% methanol in dichloromethane gave the title compound (2.7 g). LCretention time 3.44 mins

[0172] b)31,31,31-Trifluoro-1-phenyl-2,5,8,11,14,17,20,23,26,29-decaoxahentriacontane

[0173] 20,20,20-Trifluoro-3,6,9,12,15,18-hexaoxaicosan-1-ol (synthesisedin example 5(d) above) (1.15 g) and sodium hydride (60% dispersion inmineral oil, 190 mg) were suspended in tetrahydrofuran (20 mL) andstirred for 30 minutes. The product of step (a) (1.25 g) was added andthe reaction stirred for a further 15 hours. Additional quantities ofboth sodium hydride (60 mg) and product of step (a) (625 mg) were addedand the reaction stirred for a further 4 hours. Methanol (2 mL) wasadded and the reaction stirred for 30 minutes and then concentrated invacuo. The residue was partitioned between dichloromethane (200 mL) andwater (200 mL). The organic layer was collected and concentrated invacuo. Purification by chromatography on silica gel (Biotage), elutingwith cyclohexane:ethyl acetate 2:1 to remove the tosylate derivative andthen 2.5% methanol in dichloromethane gave the title compound (0.97 g).

[0174] LC retention time 3.13 mins

[0175] c)29,29,29-Trifluoro-3,6,9,12,15,18,21,24,27-nonaoxanonacosan-1-ol

[0176] A stirred solution of the product of step (b) (0.97 g) and 10%palladium on carbon (100 mg) in acetic acid:ethanol (1:9, 20 mL) wasplaced under an atmosphere of hydrogen at 20° C. for 2 hours. Thereaction mixture was filtered through a pad of celite and the solventwas removed in vacuo to give the title compound (780 mg).

[0177] LC retention time 2.45 mins

[0178] d)32,32,32-Trifluoro-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontan-1-oicacid

[0179] To a stirred solution of the product of step (c) (750 mg) intetrahydrofuran (15 mL) was added sodium hydride (60% dispersion inmineral oil, 91 mg). The reaction was stirred at 20° C. for 30 minutesthen ethyl bromoacetate (335 μl) was added and the reaction was stirredfor a further 15 hours. Ethanol (1 mL) was then added and the stirringcontinued for 5 minutes. Sodium hydroxide solution (2 M, 10 mL) wasadded and the resulting mixture was stirred at 20° C. for 30 minutes.The reaction mixture was then partitioned between dichloromethane (40mL) and water (40 mL). The aqueous layer was acidified to pH 1 by theaddition of hydrochloric acid (2 M) and then extracted withdichloromethane (2×40 mL). The combined organic layers were dried andthe solvent removed in vacuo to give the title compound as a yellow oil(612 mg).

[0180] LC retention time 2.55 mins. Mass spectrum m/z 553 [M⁺]

[0181] Experimental Data

[0182] Salmeterol xinafoate formulations in HFA 134a, of strength 25 μgper actuation, and 10% w/w (relative to drug) of the relevant surfactantcompound of formula (I) were prepared in crimped glass bottles usingsalmeterol xinafoate (8.7 mg), HFA 134a (18 g) and the relevant compound(0.87 mg). The control was prepared without the addition of asurfactant.

[0183] Table 1 shows mean particle size data determined by imageanalysis using a Galai CIS-100 particle size analyser for sampleformulations prepared as described above. In this measurement, particlesize is represented as the equivalent diameter of a circle of equal areato the object. The mean is the average of 4 determinations. The particlesize measurement was obtained by transfering the suspensions to apresurised cell, and video-imaging the sample under shear via amicroscope objective.

[0184] The equivalent diameter is defined as the diameter of a circle ofequal area to the object.${{Equivalent}\quad {Diameter}} = \sqrt{\frac{Area}{\pi}}$

[0185] The mean equivalent diameter can be weighted by number, length orvolume. e.g. For three particles with equivalent diameters of x, y andz:${{{Mean}\quad {Number}\quad {weighted}\quad {diameter}} = {{( \frac{1}{3} )x} + {( \frac{1}{3} )y} + {( \frac{1}{3} )z}}}\quad$${{Mean}\quad {Length}\quad {weighted}\quad {diameter}} = {{( \frac{x}{x + y + z} )x} + {( \frac{y}{x + y + z} )y} + \quad {( \frac{z}{x + y + z} )z}}$

[0186] The data shows that compounds of formula (I) according to theinvention have suspension stabilising properties thereby discouragingflocculation of drug particles. This is seen by the marked reduction inaverage particle size (“mean length”) when a compound of formula (I) isincorporated into the formulation. Futhermore the spread of the range ofparticles size was reduced in some cases (especially Examples 5 and 7).TABLE 1 Particle Size Data Relative Standard E.g. No. Mean Length μmStandard Deviation Deviation Control 38.8 3.0 7.8 2 27.1 2.9 10.7 6 23.72.3 9.5 5 23.8 1.2 4.9 7 28.6 1.2 4.1

[0187] Table 2 shows data relating to the total drug emitted, drugemitted ex-device and the fine particle mass fraction (FPM the sum ofstages 3 to 5) obtained using an Anderson Cascade Impactor stack. Datawere obtained at the beginning of use of the device. Salmeterolxinafoate formulations in HFA 134a, of strength 25 μg per actuation, and10% w/w (relative to drug) of the relevant surfactant compound offormula (I) were prepared in standard aluminium canisters. Control 1 wasprepared at the same time as samples containing examples 2, 5, 6 and 7whereas control 2 was prepar d separately. The analysis of aerosolformulations using such stacks is well known to person skilled in theart. The results are presented as the mean of two determinations.

[0188] The table shows that the total emitted dose and the total emittedex-device is increased for samples containing compounds of formula (I).These samples also show an increase in the absolute value of the FPMfraction in most cases. This indicates that a greater proportion of thedose will be available to reach the therapeutic target of in the lungwhich is desirable. Furthermore, advantageously the amount of overage,incorporated in the manufacturing process, to compensate for losses ofthe dose which is strictly regulated, may be reduced if more of the dosein dispensed as seen in the samples containing compounds of formula (I).TABLE 2 Total & Ex-device Emitted Dose and FPM Data Using CascadeImpaction Total Dose Total Emitted FPM E.G. No. Emitted μg Ex-Device μgμg % FPM Control 1 20.4 17.3 7.7 37.5 Control 2 19.0 15.9 7.0 36.8 222.4 18.8 8.7 38.8 5 23.0 19.4 8.6 37.2 6 21.4 17.9 7.1 33.2 7 21.9 18.48.5 38.7

[0189]FIG. 1 shows the mean cascade impaction profile of twodeteminations for salmeterol xinafoate 134a formulations containingExample 5, control 1 and control 2 the latter two being formulationswhich contain no surfactant.

[0190] Throughout the specification and the claims which follow, unlessthe context requires otherwise, the word ‘comprise’, and variations suchas ‘comprises’ and ‘comprising’, will be understood to imply theinclusion of a stated integer or step or group of integers but not tothe exclusion of any other integer or step or group of integers orsteps.

1. Use of a compound of formula (I)

or a salt or solvate thereof, wherein: n represents an integer 1 to 6; Nrepresents an integer 1 to 15; R¹ represents —(CO)_(x)C₁₋₉ alkyl or—(CO)_(x)C₁₋₉ fluoroalkyl, which fluoroalkyl moiety contains at least 1fluorine atom and not more than 3 consecutive perfluorocarbon atomswherein x represents 0 or 1; and R² and R³ independently representCl₁₋₃alkyl or hydrogen, in the preparation of pharmaceutical formulationfor inhalation therapy.
 2. A use according to claim 1 wherein R¹represents —(CO)_(x)C₁₋₅ alkyl or —(CO)_(x)C₁₋₅ fluoroalkyl, whichfluoroalkyl moiety contains at least 1 fluorine atom and not more than 3consecutive perfluorocarbon atoms.
 3. A use according to claim 2 whereinR¹ represents C₁₋₃ alkyl optionally substituted by up to 3 fluorineatoms.
 4. A use according to claim 2 wherein R¹ represents —C₀₋₆alkyleneC₁₋₃ fluoroalkyl.
 5. A use according to claim 2 wherein R¹represents —(CH₂)₃CF₂CF₃, —CH₂CF₂CF₃, —CH₂CF₃, —CF₂CF₃ or CH₃.
 6. A useaccording to any one of claims 1 to 5 wherein R² and R³ representhydrogen.
 7. A use according to any one of claims 1 to 6 wherein xrepresents
 0. 8. A use acording to claims 1 to 7 wherein n represents aninteger 1 to
 4. 9. A use according to claim 1 to 8 wherein N representsan integer 1 to
 8. 10. A use according to claim 1 which is:2,5,8,11-tetraoxatridecan-13-oic acid;2,5,8,11,14,17,20-heptaoxadocosan-22-oic acid;2,5,8,11-tetraoxahexadecan-16-oic acid;2,5,8,11,14,17,20-heptaoxapentacosan-25-oic acid;23,23,23-trifluoro-3,6,9,12,15,18,21-heptaoxatricosan-1-oic acid;{[2-({2-[(2,2,2-trifluoroethyl)oxy]ethyl}oxy)ethyl]oxy}acetic acid;2,5,8,11,14,17,20,23,26,29-decaoxahentriacontan-31-oic acid;25,25,26,26,26-pentafluoro-3,6,9, 12,15,18,21-heptaoxahexacosan-1-oicacid; (2-{2-[(4,4,5,5,5-pentafluoropentyl)oxy]ethoxy}ethoxy)acetic acid;{2-[2-(2,2,3,3,3-pentafluoropropoxy)ethoxy]ethoxy}acetic acid;23,23,24,24,24-pentafluoro-3,6,9, 12,15,18,21-heptaoxatetracosan-1-oicacid;32,32,32-trifluoro-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontan-1-oicacid; or a salt or solvate of any one thereof.
 11. A use according toany one of claims 1 to 10 in the form of the free acid.
 12. A compoundof formula (I) as defined in claim 1 wherein R¹ represents —C₀₋₆alkyleneC₁₋₃ fluoroalkyl which fluoroalkyl moiety contains at least 1fluorine atom and not more than 3 consecutive perfluorocarbon atoms. 13.A compound of formula (I) as defined in claim 1, which is2,5,8,11,14,17,20-heptaoxadocosan-22-oic-acid;2,5,8,11-tetraoxatridecan-16-oic acid;2,5,8,11,14,17,20-heptaoxadocosan-25-oic acid;23,23,23-trifluoro-3,6,9,12,15,18,21-heptaoxatricosan-1-oic acid;{[2-({2-[(2,2,2-trifluoroethyl)oxy]ethyl}oxy)ethyl]oxy}acetic acid;2,5,8,11,14,17,20,23,26,29-decaoxahentriacontan-31-oic acid;25,25,26,26,26-pentafluoro-3,6,9, 12,15,18,21-heptaoxahexacosan-1-oicacid; (2-{2-[(4,4,5,5,5-pentafluoropentyl)oxy]ethoxy}ethoxy)acetic acid;{2-[2-(2,2,3,3,3-pentafluoropropoxy)ethoxy]ethoxy}acetic acid;23,23,24,24,24-pentafluoro-3,6,9,12,15,18,21-heptaoxatetracosan-1-oicacid;32,32,32-trifluoro-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontan-1-oicacid; or a salt or solvate of any one thereof.